This invention is directed to substituted azaindoles, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of the protein kinases.
Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [S. K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages 576-596]. The serine/threonine kinases include for example, protein kinase C isoforms [A. C. Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S. Iwashita and M. Kobayashi, Cellular Signalling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C. Chan et. al., Ann. Rev. Immunol., 1994, l2, pages 555-592].
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
Syk is a 72-kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of hematopoietic cells and is an essential element in several cascades that couple antigen receptors to cellular responses. Thus, Syk plays a pivotal role in signalling of the high affinity IgE receptor, Fcxcex5R1, in mast cells and in receptor antigen signalling in T and B lymphocytes. The signal transduction pathways present in mast, T and B cells have common features. The ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity. However, they interact with transducing subunits that contain immunoreceptor tyrosine based activation motifs (ITAMs) [M. Reth, Nature, 1989, 338, pages 383-384]. These motifs are present in both the xcex2 and xcex3 subunits of the Fcxcex5R1, in the "xgr"-subunit the of T cell receptor (TCR) and in the IgGxcex1 and IgG xcex2 subunits of the B cell receptor (BCR). [N. S. van Oers and A. Weiss, Seminars in Immunology, 1995, 7, pages 227-236] Upon binding of antigen and multimerization, the ITAM residues are phosphorylated by protein tyrosine kinases of the Src family. Syk belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of Syk with an activated receptor stimulates Syk kinase activity and localises Syk to the plasma membrane.
In Syk deficient mice, mast cell degranulation is inhibited, suggesting that this is an important target for the development of mast cell stabilising agents [P. S. Costello, Oncogene, 1996, 13, pages 2595-2605]. Similar studies have demonstrated a critical role for Syk in BCR and TCR signalling [A. M. Cheng, Nature, 1995, 378, pages 303-306, (1995) and D. H. Chu et al., Immunological Reviews, 1998, 165, pages 167-180]. Syk also appears to be involved in eosinophil survival in response to IL-5 and GM-CSF [S. Yousefi et al., J. Exp. Med., 1996, 183, pages 1407-1414]. Despite the key role of Syk in mast cell, BCR and T cell signalling, little is known about the mechanism by which Syk transmits downstream effectors. Two adaptor proteins, BLNK (B cell Linker protein, SLP-65) and SLP-76 have been shown to be substrates of Syk in B cells and mast cells respectively and have been postulated to interface Syk with downstream effectors [M. Ishiai et al., Immunity, 1999, 10, pages 117-125 and L. R. Hendricks-Taylor et al., J.Biol. Chem, 1997, 272, pages 1363-1367]. In addition Syk appears to play an important role in the CD40 signalling pathway, which plays an important role in B cell proliferation [M. Faris et al., J.Exp. Med., 1994, 179, pages 1923-1931].
Syk is further involved in the activation of platelets stimulated via the low-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [F. Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471-478].
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways. FAK colocalizes with integrins in focal contact sites and FAK activation and its tyrosine phosphorylation have been shown in many cell types to be dependent on integrins binding to their extracellular ligands. Results from several studies support the hypothesis that FAK inhibitors could be useful in cancer treatment. For example, FAK-deficient cells migrate poorly in response to chemotactic signals and overexpression of C-terminal domain of FAK blocks cell spreading as well as chemotactic migration (Sieg et al, J. Cell Science,1999, 112, 2677-2691; Richardson A. and Parsons T., Cell, 1997, 97, 221-231); in addition, tumor cells treated with FAK antisense oligonucleotides lost their attachment and underwent apoptosis (Xu et al, Cell Growth Differ. 1996, 4, 413-418). FAK has been reported to be overexpressed in prostate, breast, thyroid, colon and lung cancers. The level of expression of FAK is directly correlated with tumors demonstrating the most aggressive phenotype.
Angiogenesis or the formation of new blood vessels by sprouting from the preexisting vasculature is of central importance for embryonic development and organogenesis. Abnormal enhanced neovascularization is observed in rheumatoid arthritis, diabetic retinopathy and during tumor development (Folkman, Nat. Med., 1995, 1, 27-31.). Angiogenesis is a complex multistage process which includes activation, migration, proliferation and survival of endothelial cells. Extensive studies in the field of tumor angiogenesis in the past two decades have identified a number of therapeutic targets including kinases, proteases and integrins resulting in the discovery of many new anti-angiogenic agents, including KDR inhibitors some of which are currently under clinical evaluation (Jekunen, et al Cancer Treatment Rev. 1997, 23, 263-286.). Angiogenesis inhibitors may be used in frontline, adjuvant and even preventive settings for the emergence or regrowth of malignancies.
Several proteins involved in chromosome segregation and spindle assembly have been identified in yeast and drosophila. Disruption of these proteins results in chromosome missegregation and monopolar or disrupted spindles. Among these kinases are the Ipl1 and aurora kinases from S. cerevisiae and drosophila respectively, which are required for centrosome separation and chromosome segregation. One human homologue of yeast Ipl1 was recently cloned and characterized by different laboratories. This kinase termed Aurora2, STK15 or BTAK belongs to the serine/threonine kinase family. Bischoff et al showed that Aurora2 is oncogenic and is amplified in human colorectal cancers (EMBO J, 1998, 17, 3052-3065). It has also been exemplified in cancers involving epithelial tumors such as breast cancer.
We have now found a novel group of substituted azaindoles, which have valuable pharmaceutical properties, in particular, the ability to inhibit protein kinases, more particularly, the ability to selectively inhibit Syk kinase.
Thus, in one aspect, the present invention is directed to pharmaceutical compositions comprising compounds of general formula (I): 
wherein:
R1 represents aryl or heteroaryl each optionally substituted by one or more groups selected from acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R4, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, xe2x80x94C(xe2x95x90O)xe2x80x94OR5, xe2x80x94NY1Y2, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94NY3Y4, xe2x80x94SO2xe2x80x94NY1Y2 and xe2x80x94Z2R4;
R2 represents hydrogen, acyl, cyano, halo, lower alkenyl or lower alkyl optionally substituted by a substituent selected from cyano, heteroaryl, heterocycloalkyl, xe2x80x94Z1R8, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, xe2x80x94CO2R8, xe2x80x94NY3Y4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94OR7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94NY3Y4 and one or more halogen atoms;
R3 represents hydrogen, aryl, cyano, halo, heteroaryl, lower alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94OR5 or xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y;
R4 represents alkyl, cycloalkyl or cycloalkylalkyl each optionally substituted by a substituent selected from aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, xe2x80x94CHO (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, xe2x80x94C(xe2x95x90O)xe2x80x94OR5, xe2x80x94NY1Y2, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94NY3Y4, xe2x80x94OR7 and one or more groups selected from hydroxy and carboxy;
R5 represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R6 represents hydrogen or lower alkyl;
R7 represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R8 represents hydrogen or lower alkyl;
X1 represents N, CH, C-halo, Cxe2x80x94CN, Cxe2x80x94R7, Cxe2x80x94NY3Y4, Cxe2x80x94OH, Cxe2x80x94Z2R7, Cxe2x80x94C(xe2x95x90O)xe2x80x94OR5, Cxe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, Cxe2x80x94N(R8)xe2x80x94C(xe2x95x90O)xe2x80x94R7, Cxe2x80x94SO2xe2x80x94NY3Y4, Cxe2x80x94N(R8)xe2x80x94SO2xe2x80x94R7, C-alkenyl, C-alkynyl or Cxe2x80x94NO2;
Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl optionally substituted by one or more groups selected from aryl, halo, heteroaryl, hydroxy, xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, xe2x80x94C(xe2x95x90O)xe2x80x94OR5, xe2x80x94NY3Y4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94NY3Y4 and xe2x80x94OR7; or the group xe2x80x94NY1Y2 may form a cyclic amine;
Y3 and Y4 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group xe2x80x94NY3Y4 may form a cyclic amine;
Z1 represents O or S;
Z2 represents O or S(O)n;
n is zero or an integer 1 or 2;
and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and
pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and their prodrugs, and their acid bioisosteres; together with one or more pharmaceutically acceptable carriers or excipients.
In another aspect, the invention concerns the compounds of formula (I) as defined above, but excluding the compounds 2-phenyl-1H-pyrrolo[2,3-b]pyridine, 2-(4-bromo-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid methyl ester, 2-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine, 2-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 5-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 4-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 2-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid, 2-(4-methoxy-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 2-(4-methyl-phenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine, 4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-benzoic acid isopropyl ester, 2-phenyl-3-methyl-1H-pyrrolo[2,3-b]pyridine, 5-bromo-2-phenyl-3-methyl-1H-pyrrolo[2,3-b]pyridine, 6-chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 6-chloro-4-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, 4-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl-carboxaldehyde, 2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl-acetonitrile, 2-phenyl-3-prop-1-enyl-1H-pyrrolo[2,3-b]pyridine, 4-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl-carboxaldehyde, dimethyl-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine, 2,2xe2x80x2-diphenyl-1H,1xe2x80x2H-[3,3xe2x80x2]bi[pyrrolo[2,3-b]pyridinyl], 2-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetamide, 3-allyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, (2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile, 2-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde, 3-morpholin-4-ylmethyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, N-[2-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-acetamide, 6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 6-(4-methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 6-(4-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 6-(2-chloro-phenyl)-5H-pyrrolo[2,3-b]pyrazine, 3-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine, 2-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine and 7-methyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993, 33, pages 576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995, pages 34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995, 343, pages 105-109 xe2x80x9cTheoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. xe2x80x9cBranched,xe2x80x9d as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenyloxyxe2x80x9d is an alkenyl-Oxe2x80x94 group wherein alkenyl is as defined above. Exemplary alkenyloxy groups include allyloxy.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. xe2x80x9cLower alkylxe2x80x9d as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branched chain having 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl. Exemplary alkyl groups substituted by one or more halogen atoms include trifluoromethyl.
xe2x80x9cAlkylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.
xe2x80x9cAlkylenedioxyxe2x80x9d means an xe2x80x94O-alkylene-Oxe2x80x94 group in which alkylene is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulfonyl groups are those in which the alkyl group is C1-4alkyl;
xe2x80x9cAlkylsulfonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl, group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which group may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Except where otherwise defined, aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, xe2x80x94NY3Y4, xe2x80x94CONY3Y4, xe2x80x94SO2NY3Y4, xe2x80x94NY3xe2x80x94C(xe2x95x90O)alkyl, xe2x80x94NY3SO2alkyl or alkyl optionally: substituted with aryl, heteroaryl, hydroxy, or xe2x80x94NY3Y4.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkyl-Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy, each optionally substituted.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulfonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAzaheteroarylxe2x80x9d means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are selected from carbon, oxygen, sulfur, and nitrogen. Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, indazolinyl, indolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, quinazolinyl and tetrahydroindolizinyl.
xe2x80x9cCyclic aminexe2x80x9d means a 3 to 8 membered monocyclic cycloalkyl ring system wherein one of the ring carbon atoms is replaced by nitrogen and which (i) may also contain a further heteroatom-containing group selected from O, S, SO2, or NY7 (where Y7 is hydrogen, alkyl, aryl, arylalkyl, xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94C(xe2x95x90O)xe2x80x94OR7 or xe2x80x94SO2R7); and (ii) may be fused to additional aryl (e.g. phenyl), heteroaryl (e.g. pyridyl), heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro and chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as described herein. Exemplary heteroaryl groups include pyridylcarbonyl.
xe2x80x9cHeteroaroylaminoxe2x80x9d means a heteroaroyl-NHxe2x80x94 group in which the heteroaryl moiety is as previously described.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above except where otherwise defined); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups, optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, except where otherwise defined). Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, except where otherwise defined.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylsulfonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocycloalkylxe2x80x9d means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and NY7 and mat be optionally substituted by oxo; (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted by one or more xe2x80x9caryl group substituents,xe2x80x9d and a heterocycloalkyl group are fused together to form a cyclic structure. (Examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively, an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of compounds of formula (I) containing a hydroxy group are, for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
Suitable esters of compounds of formula (I) containing a carboxy group are, for example, those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379.
Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety xe2x80x94L1xe2x80x94Y include lactones formed by loss of water between said carboxy and hydroxy groups. Examples of such lactones include caprolactones and butyrolactones.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent optionally substituted heteroaryl, especially optionally substituted azaheteroaryl. Exemplary optionally substituted azaheteroaryls include indolyl, furanyl, pyridyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, imidazolyl, indazolyl, indolizinyl, tetrahydroindolizinyl and indazolinyl. Optional substituents include one or more groups selected from alkylenedioxy, alkenyl, alkenyloxy, aryl, carboxy (or an acid bioisostere), cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, R4, xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, xe2x80x94NY1Y2 and xe2x80x94OR4. R1 more preferably represents optionally substituted indolyl, optionally substituted indolizinyl or optionally substituted pyrrolyl and is more especially optionally substituted indol-3-yl, indolizin-1-yl or optionally substituted pyrrol-3-yl.
R1 may also particularly represent optionally substituted aryl, especially optionally substituted phenyl. Optional substituents include one or more groups selected from alkylenedioxy, halo, R4, xe2x80x94NY1Y2 and xe2x80x94OR4. R1 still more preferably represents 4-substituted phenyl, more especially 4-tertiarybutylphenyl,
R2 may particularly represent hydrogen.
R2 may also particularly represent halo.
R2 may also particularly represent lower alkyl optionally substituted by carboxy, cyano, halo, hydroxy, tetrazolyl, or xe2x80x94CONY3Y4.
R2 may also particularly represent lower alkenyl.
R3 may particularly represent hydrogen.
R3 may also particularly represent optionally substituted aryl, especially optionally substituted phenyl.
R3 may also particularly represent lower alkyl (e.g. methyl).
X1 may particularly represent N.
X1 may also particularly represent CH.
X1 may also particularly represent C-lower alkoxy, especially Cxe2x80x94OCH3.
X1 may also particularly represent C-aryl, especially C-phenyl.
X1 may also particularly represent C-halo, especially Cxe2x80x94Cl.
X1 may also particularly represent Cxe2x80x94CN.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular preferred group of compounds of the invention are compounds of formula (Ia): 
in which R2, R3 and X1 are as hereinbefore defined; R9 is hydrogen, R4, alkenyl or heterocycloalkyl; R10 is alkenyloxy, carboxy (or an acid bioisostere), cyano, halo, hydroxy, heteroaryl, R4, xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, xe2x80x94OR4, xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7, xe2x80x94N(R6)xe2x80x94SO2xe2x80x94R7 or xe2x80x94NY1Y2; and p is zero, or an integer 1 or 2; and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ia) and their prodrugs.
Compounds of formula (Ia) in which R2 represents hydrogen are preferred.
Compounds of formula (Ia) in which R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen, are preferred.
Compounds of formula (Ia) in which X1 is CH, C-lower alkoxy (e.g. Cxe2x80x94OCH3), C-aryl, (e.g. C-phenyl), C-halo (e.g. Cxe2x80x94Cl), Cxe2x80x94CN or N are preferred.
Compounds of formula (Ia) in which R9 represents:
(i) hydrogen;
(ii) C1-4alkyl [e.g. xe2x80x94CH3];
(iii) C1-4alkyl substituted by hydroxy [e.g. xe2x80x94CH2OH, xe2x80x94CH2CH2OH or xe2x80x94CH2CH2CH2OH];
(iv) C1-4alkyl substituted by xe2x80x94N(R6)C(xe2x95x90O)xe2x80x94R7 [e.g. xe2x80x94CH2CH2CH2NHC(xe2x95x90O)CH3];
(v) C1-4alkyl substituted by xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 e.g. 
(vi) cycloalkylalkyl substituted by hydroxy 
are preferred. Compounds of formula (Ia) in which R9 represents hydrogen or xe2x80x94CH3 are especially preferred.
Compounds of formula (Ia) in which R10 represents:
(i) hydroxy;
(ii) xe2x80x94OR4 in which R4 is alkyl [e.g. xe2x80x94OCH3];
(iii) xe2x80x94OR4 in which R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups [e.g. xe2x80x94OCH2CH2OH, xe2x80x94OCH2CH2CH2OH, xe2x80x94OCH(CH3)CH2OH, 
(iv) xe2x80x94OR4 in which R4 is alkyl substituted by one or more alkoxy groups [e.g. xe2x80x94OCH(CH3)CH2OCH3];
(v) xe2x80x94OR4 in which R4 is alkyl or cycloalkyl substituted by one or more carboxy groups 
(vi) xe2x80x94OR4 in which R4 is cycloalkyl substituted by xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2
(vii) xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7 [e.g. xe2x80x94NHC(xe2x95x90O)CH3];
(viii) xe2x80x94CONY1Y2 [e.g. xe2x80x94CONH2, xe2x80x94CONHCH3, xe2x80x94CONHCH(CH2OH)2, xe2x80x94CONHCH2CH2OH, xe2x80x94CONHC(CH3)2CH2OH, xe2x80x94CONHCH2CH2OCH3, xe2x80x94CONHCH2CH2CO2H, CONHCH2CH2CONH2 or 
(ix) carboxy
(x) alkyl substituted by carboxy [e.g. xe2x80x94CH2CH2CO2H];
(xi) heteroaryl 
(xii) xe2x80x94C(xe2x95x90O)xe2x80x94R4 in which R4 is alkyl [e.g. xe2x80x94C(xe2x95x90O)xe2x80x94CH3]; or
are preferred. Compounds of formula (Ia) in which R10 represents xe2x80x94OCH3, 
are especially preferred.
When p is 1, R10 is preferably attached to position 5 of the indolyl ring.
When p is 2, the R10 groups are preferably attached to positions 5 and 6 of the indolyl ring.
A preferred group of compounds of the invention are compounds of formula (Ia) in which: R2 is hydrogen; R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen; X1 is CH, C-lower alkoxy [especially Cxe2x80x94OCH3], C-aryl [especially C-phenyl], C-halo [especially Cxe2x80x94Cl] or Cxe2x80x94CN; R9 is (i) hydrogen, (ii) C1-4alkyl [e.g. xe2x80x94CH3], (iii) C1-4alkyl substituted by hydroxy [e.g. xe2x80x94CH2OH, xe2x80x94CH2CH2OH or xe2x80x94CH2CH2CH2OH], (iv) C1-4alkyl substituted by xe2x80x94N(R6)C(xe2x95x90O)xe2x80x94R7 [e.g. xe2x80x94CH2CH2CH2NHC(xe2x95x90O)CH3], (v) C1-4alkyl substituted by xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2
or (vi) cycloalkylalkyl substituted by hydroxy 
R10 is (i) hydroxy, (ii) xe2x80x94OR4 in which R4 is alkyl [e.g. xe2x80x94OCH3], (iii) xe2x80x94OR4 in which R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups [e.g. xe2x80x94OCH2CH2OH, xe2x80x94OCH2CH2CH2OH, xe2x80x94OCH2CH (OH)CH2OH, xe2x80x94OCH2CH(OH)CH3, xe2x80x94OCH(CH3)CH2OH or 
(iv) xe2x80x94OR4 in which R4 is alkyl substituted by one or more alkoxy groups [e.g. xe2x80x94OCH(CH3)CH2OCH3], (v) xe2x80x94OR4 in which R4 is alkyl or cycloalkyl substituted by one or more carboxy groups [e.g. xe2x80x94OCH2CO2H, xe2x80x94OCH(CH3)CO2H or 
(vi) xe2x80x94OR4 in which R4 is cycloalkyl substituted by xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 
(vii) xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7 [e.g. xe2x80x94NHC(xe2x95x90O)CH3]; (viii) xe2x80x94CONY1Y2 [e.g. xe2x80x94CONH2, xe2x80x94CONHCH3, xe2x80x94CONHCH(CH2OH)2, xe2x80x94CONHCH2CH2OH, xe2x80x94CONHC(CH3)2CH2OH, xe2x80x94CONHCH2CH2OCH3, xe2x80x94CONHCH2CH2CO2H, xe2x80x94CONHCH2CH2CONH2 or 
(ix) carboxy, (x) alkyl substituted by carboxy [e.g. xe2x80x94CH2CH2CO2H], (xi) heteroaryl 
(xii) xe2x80x94C(xe2x95x90O)xe2x80x94R4 in which R4 is alkyl [e.g. xe2x80x94C(xe2x95x90O)xe2x80x94CH3] or (xii) tetrazolyl or N-methyltetrazolyl; the R10 group is attached to position 5 of the indolyl ring when p is 1 and the R10 groups are attached to position 5 and 6 of the indolyl ring when p is 2; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
A further preferred group of compounds of the invention are compounds of formula (Ia) in which: R2 is hydrogen; R3 is hydrogen or lower alkyl (e.g. methyl), especially hydrogen; X1 is N; R9 is (i) hydrogen, (ii) C1-4alkyl [e.g. xe2x80x94CH3], (iii) C1-4alkyl substituted by hydroxy [e.g. xe2x80x94CH2OH, xe2x80x94CH2CH2OH or xe2x80x94CH2CH2CH2OH], (iv) C1-4alkyl substituted by xe2x80x94N(R6)C(xe2x95x90O)xe2x80x94R7 [e.g. xe2x80x94CH2CH2CH2NHC(xe2x95x90O)CH3], (v) C1-4alkyl substituted by xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2
or (vi) cycloalkylalkyl substituted by hydroxy 
R10 is (i) hydroxy, (ii) xe2x80x94OR4 in which R4 is alkyl [e.g. xe2x80x94OCH3] (iii) xe2x80x94OR4 in which R4 is alkyl or cycloalkylalkyl substituted by one or more hydroxy groups [e.g. xe2x80x94OCH2CH2OH, xe2x80x94OCH2CH2CH2OH, xe2x80x94OCH2CH(OH)CH2OH, xe2x80x94OCH2CH(OH)CH3, xe2x80x94OCH(CH3)CH2OH or 
(iv) xe2x80x94OR4 in which R4 is alkyl substituted by one or more alkoxy groups [e.g. xe2x80x94OCH(CH3)CH2OCH3], (v) xe2x80x94OR4 in which R4 is alkyl or cycloalkyl substituted by one or more carboxy groups [e.g. xe2x80x94OCH2CO2H, xe2x80x94OCH(CH3)CO2H or 
(vi) xe2x80x94OR4 in which R4 is cycloalkyl substituted by xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 [e.g. 
(vii) xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94R7 [e.g. xe2x80x94NHC(xe2x95x90O)CH3]; (viii) xe2x80x94CONY1Y2 [e.g. xe2x80x94CONH2, xe2x80x94CONHCH3,xe2x80x94CONHCH(CH2OH)2, xe2x80x94CONHCH2CH2OH, xe2x80x94CONHC(CH3)2CH2OH, xe2x80x94CONHCH2CH2OCH3, xe2x80x94CONHCH2CH2CO2H, xe2x80x94CONHCH2CH2CONH2 or 
(ix) carboxy, (x) alkyl substituted by carboxy [e.g. xe2x80x94CH2CH2CO2H], (xi) heteroaryl 
(xii) xe2x80x94C(xe2x95x90O)xe2x80x94R4 in which R4 is alkyl [e.g. xe2x80x94C(xe2x95x90O)xe2x80x94CH3] or (xii) tetrazolyl or N-methyltetrazolyl; the R10 group is attached to position 5 of the indolyl ring when p is 1 and the R10 groups are attached to position 5 and 6 of the indolyl ring when p is 2; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another particular group of compounds of the invention are compounds of formula (Ib): 
in which R2, R3, R9, R10, X1 and p are as hereinbefore defined, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ib) and their prodrugs.
Compounds of formula (Ib) in which R2 represents hydrogen are preferred.
Compounds of formula (Ib) in which R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen, are preferred.
Compounds of formula (Ib) in which X1 is CH, C-lower alkoxy (e.g. Cxe2x80x94OCH3), C-aryl, (e.g. C-phenyl), C-halo (e.g. Cxe2x80x94Cl), Cxe2x80x94CN or N are preferred.
Compounds of formula (Ib) in which R9 represents hydrogen are preferred.
Compounds of formula (Ib) in which R9 represents C1-4alkyl [e.g. xe2x80x94CH3] are also preferred.
Compounds of formula (Ib) in which p is zero are preferred.
A preferred group of compounds of the invention are compounds of formula (Ib) in which: R2 is hydrogen; R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen; X1 is CH, C-lower alkoxy [especially Cxe2x80x94OCH3], C-aryl [especially C-phenyl], C-halo [especially Cxe2x80x94Cl] or Cxe2x80x94CN; R9 is hydrogen or C1-4alkyl [e.g. xe2x80x94CH3]; p is zero; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
A further preferred group of compounds of the invention are compounds of formula (Ib) in which: R2 is hydrogen; R3 is hydrogen or lower alkyl (e.g. methyl), especially hydrogen; X1 is N; R9 is hydrogen or C1-4alkyl [e.g. xe2x80x94CH3]; p is zero; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another particular group of compounds of the invention are compounds of formula (Ic): 
in which R2, R3, R9, R10, X1 and p are as hereinbefore defined, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ic) and their prodrugs.
Compounds of formula (Ic) in which R2 represents hydrogen are preferred.
Compounds of formula (Ic) in which R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen, are preferred.
Compounds of formula (Ic) in which X1 is CH, C-lower alkoxy (e.g. Cxe2x80x94OCH3), C-aryl, (e.g. C-phenyl), C-halo (e.g. Cxe2x80x94Cl), Cxe2x80x94CN or N are preferred.
Compounds of formula (Ic) in which R9 represents C1-4alkyl [e.g. xe2x80x94CH3] are also preferred.
Compounds of formula (Ic) in which p is 1 are preferred.
Compounds of formula (Ic) in which R10 represents aryl [e.g. phenyl] are preferred.
R10 is preferably attached at position 4 of the pyrrole ring.
A preferred group of compounds of the invention are compounds of formula (Ic) in which: R2 is hydrogen; R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen; X1 is CH, C-lower alkoxy [especially Cxe2x80x94OCH3], C-aryl [especially C-phenyl], C-halo [especially Cxe2x80x94Cl] or Cxe2x80x94CN; R9 is C1-4alkyl [e.g. xe2x80x94CH3]; p is 1; R10 is aryl [e.g. phenyl] and R10 is attached at position 4 of the pyrrole ring; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs. R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen; X1 is CH, C-lower alkoxy [especially Cxe2x80x94OCH3], C-aryl [especially C-phenyl], C-halo [especially Cxe2x80x94Cl] or Cxe2x80x94CN;
A further preferred group of compounds of the invention are compounds of formula (Ic) in which: R2 is hydrogen; R3 is hydrogen; X1 is N; R9 is C1-4alkyl [e.g. xe2x80x94CH3]; p is 1; R10 is aryl [e.g. phenyl] and R10 is attached at position 4 of the pyrrole ring; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another particular group of compounds of the invention are compounds of formula (Id): 
in which R2, R3, R10, X1 and p are as hereinbefore defined, and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Id) and their prodrugs.
Compounds of formula (Id) in which R2 represents hydrogen, lower alkyl (e.g. methyl), lower alkyl substituted by xe2x80x94CONY3Y4 (e.g. xe2x80x94CH2CH2CONH2 or xe2x80x94CH2CH2CONHCH3), lower alkyl substituted by carboxy (e.g. xe2x80x94CH2CH2CO2H), lower alkyl substituted by tetrazolyl 
or lower alkyl substituted by hydroxy [e.g. xe2x80x94CH2CH2CH2OH] are preferred.
Compounds of formula (Id) in which R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen, are preferred.
Compounds of formula (Id) in which X1 is CH, C-lower alkoxy (e.g. Cxe2x80x94OCH3), C-aryl, (e.g. C-phenyl), C-halo (e.g. Cxe2x80x94Cl), Cxe2x80x94CN or N are preferred.
Compounds of formula (Id) in which p is 1 are preferred.
Compounds of formula (Id) in which R10 represents alkyl [e.g. tertiarybutyl] are preferred.
R10 is preferably attached at position 4.
A preferred group of compounds of the invention are compounds of formula (Id) in which: R2 is hydrogen, lower alkyl (e.g. methyl), lower alkyl substituted by xe2x80x94CONY3Y4 (e.g. xe2x80x94CH2CH2CONH2 or xe2x80x94CH2CH2CONHCH3), lower alkyl substituted by carboxy (e.g. xe2x80x94CH2CH2CO2H), lower alkyl substituted by tetrazolyl 
or lower alkyl substituted by hydroxy [e.g. xe2x80x94CH2CH2CH2OH]; R3 is hydrogen, optionally substituted aryl (e.g. phenyl) or lower alkyl (e.g. methyl), especially hydrogen; X1 is CH, C-lower alkoxy [especially Cxe2x80x94OCH3], C-aryl [especially C-phenyl], C-halo [especially Cxe2x80x94Cl] or Cxe2x80x94CN; p is 1; R10 is alkyl [e.g. tertiary-butyl] and R10 is attached at position 4; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
A further preferred group of compounds of the invention are compounds of formula (Id) in which: R2 is hydrogen, lower alkyl (e.g. methyl), lower alkyl substituted by xe2x80x94CONY3Y4 (e.g. xe2x80x94CH2CH2CONH2 or xe2x80x94CH2CH2CONHCH3), lower alkyl substituted by carboxy (e.g. xe2x80x94CH2CH2CO2H), lower alkyl substituted by tetrazolyl 
or lower alkyl substituted by hydroxy [e.g. xe2x80x94CH2CH2CH2OH]; R3 is hydrogen; X1 is N; p is 1; R10 is alkyl [e.g. tertiary-butyl] and R10 is attached at position 4; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Particular compounds of the invention of formula (Ia) are selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A1 to A28) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the fragments (B1 to B19) shown in Table 2, and joining the carbon atom (C*) of the phenyl ring in one of the fragments (B1 to B19) shown in Table 2 to the oxygen atom (*O) of one of the fragments (C1 to C19) depicted in Table 3.
Particular compounds of the invention of formula (Ia) are also selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A1 to A28) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the fragments (B1 to B19) shown in Table 2, and joining the carbon atom (C*) of the phenyl ring in one of the fragments (B1 to B19) shown in Table 2 to the carbon atom (*C) of one of the fragments (C20 to C44) depicted in Table 3.
Particular compounds of the invention of formula (Ia) are also selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A1 to A28) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the fragments (B1 to B19) shown in Table 2, and joining the carbon atom (C*) of the phenyl ring in one of the fragments (B1 to B19) shown in Table 2 to the nitrogen atom (*N) of the fragment (C45) or a hydrogen atom (*H, fragment (C46)) depicted in Table 3.
Particular compounds of the invention of formula (Ib) are selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A1 to A28) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the indolizine fragments (B20 or B21) shown in Table 2, and joining the carbon atom (C*) in the six membered ring of one of the indolizine fragments (B20 or B21) shown in Table 2 to (i) the oxygen atom (*O) of one of the fragments (C1 to C19), (ii) the carbon atom (*C) of one of the fragments (C20 to C42), (iii) the nitrogen atom (*N) of the fragment (C45) or (iv) a hydrogen atom (*H, fragment (C46)) depicted in Table 3.
Particular compounds of the invention of formula (Ib) are also selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A1 to A28) shown in Table 1 to the carbon atom (*C) in the indolizine fragments (B22) shown in Table 2.
Particular compounds of the invention of formula (Ic) are selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A1 to A28) shown in Table 1 to the carbon atom (*C) in one of the pyrrole fragments (B23 to B32) shown in Table 2.
Particular compounds of the invention of formula (Id) are selected from the compounds formed by joining the carbon atom (C*) of one of the azaindoles fragments (A29 to A41) shown in Table 1 to the carbon atom (*C) in one of the fragments (B33 to B44) shown in Table 2.
Thus, for example, in the above list the compound denoted as A1-B1-C1 is the product of the combination of group A1 in Table 1 and B1 in Table 2 and C1 in Table 3, namely 
Example 1(a) hereinafter described.
Particular compounds of the invention are:
6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(3-bromophenyl)-5H-pyrrolo[2,3-b]pyrazine;
7-iso-propyl-6-phenyl-5H-pyrrolo[2,3-b]pyrazine;
2-(4-bromophenyl)-1H-pyrrolo[2,3-b]pyrazine;
6-(4-[1,3]dioxan-2-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(3-[1,3]dioxan-2-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazine;
2-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-quinoline;
3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-isoquinoline;
6-[1-methyl-1H-indol-5-yl]-5H-pyrrolo[2,3-b]pyrazine;
6-(5-methoxy-1-methyl-1H-indol-3-yl)-2-methyl-5H-pyrrolo[2,3-b]pyrazine;
3-methyl-6-(1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-benzyl-5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-methyl-1H-pyrrol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-methyl-1H-pyrrol-2-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-indolizin-1-yl-5H-pyrrolo[2,3-b]pyrazine;
6-(3-methyl-indolizin-1-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(3-methyl-5-phenyl-1H-pyrrol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(5,6,7,8-tetrahydro-indolizin-1yl)-5H-pyrrolo[2,3-b]pyrazine;
6-furan-3-yl-5H-pyrrolo[2,3-b]pyrazine;
dimethyl-[4-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-amine;
6-(5-methoxy-1-methyl-1H-indol-3-yl)-7-methyl-5H-pyrrolo[2,3-b]pyrazine;
6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(4-tert-butylphenyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazine;
6-(3,4-dimethoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(4-aminophenyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazine;
6-[4-(1-methyl)ethoxyphenyl]-5H-pyrrolo[2,3-b]pyrazine;
6-(1H-1-methyl-2-(methylthio)imidazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(4-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine;
7-(prop-2-enyl)-6-[4-(tert-butyl)phenyl]-5H-pyrrolo[2,3-b]pyrazine;
6-(4-methylthiophenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(3-methoxylphenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine;
6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine;
3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol;
3-[5-methoxy-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol;
2-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-ethanol;
2-[5-methoxy-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-ethanol;
3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylamine;
3-[5-methoxy-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylamine;
N-{3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propyl}-acetamide;
6-[1-(3-morpholin-4-yl-propyl)-1H-indol-3-yl]-5H-pyrrolo[2,3-b]pyrazine;
6-[1-(3-piperidin-1-yl-propyl)-1H-indol-3-yl]-5H-pyrrolo[2,3-b]pyrazine;
6-{1-[3-(pyridin-3-yloxy)-propyl]-1H-indol-3-yl}-5H-pyrrolo[2,3-b]pyrazine;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-ol;
6-(2-chloro-5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-benzaldehyde;
4-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-benzaldehyde;
[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-methanol;
[4-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-methanol;
6-(5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine;
2-[5-methoxy-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-1-morpholin-4-yl-ethanone;
[5-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-acetic acid;
4-methoxy-2-(5-methoxy-3-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
4-methoxy-2-(5-methoxy-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
4-chloro-2-(4-tertiary-butylphenyll)-1H-pyrrolo[2,3-b]pyridine;
5-phenyl-2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-[5-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-1-morpholin-4-yl-ethanone;
1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-cyclobutanecarboxylic acid amide;
1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-cyclobutanecarboxylic acid methylamide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid methylamide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2-hydroxy-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2-carbamoyl-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid bis-(2-hydroxy-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2,3-dihydroxy-propyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid (2-hydroxy-1,1-dimethylethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yI)-1H-indole-5-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-6-carboxylic acid (2-carbamoyl-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-6-carboxylic acid (2-hydroxy-ethyl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-6-carboxylic acid (1H-[1,2,4]triazol-3-yl)-amide;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-6-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;
3-[6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-N-methylpropionamide;
3-[6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-N,N-dimethylpropionamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid 2-methoxyethylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid 2-thien-2-ylethylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid 2-fluoroethylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid 2-carboethoxyethylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid (hydroxymethyl)-carbomethoxy-methylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid 2-hydroxyethylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid methylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid dimethylamide;
[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yl]morpholin-4-yl ketone;
4-hydroxy-[1-[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yl]carbonylpiperidine
3-[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yl]carbonylaminopropionic acid methylamide;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid 3-hydroxypropylamide;
3-{6-[4-(1-methyl)ethoxyphenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionic acid methylamide;
3-[6-(4-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]propionic acid methylamide;
3-{6-[4-(1-methyl)ethoxyphenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionamide;
3-{6-(4-hydroxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionamide;
3-[6-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]propionic acid methylamide;
[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-acetic acid;
2-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-propionic acid;
1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-cyclobutanecarboxylic acid;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-ol;
1-{1-(cyclobutanecarboxylic acid)-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yloxy}-cyclobutanecarboxylic acid;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-6-carboxylic acid;
3-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-propionic acid;
1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indole-5-carboxylic acid;
[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenoxy]acetic acid;
3-[2-dimethylamino-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]propionic acid;
2-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-ethanol;
2-[-methyl-3-(1H-pyrrolo[2,3-b]pyrdin-2-yl)-1H-indol-5-yloxyl-propan-1-ol;
{1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-cyclobutyl}-methanol;
2-(6-phenyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-ethanol;
3-[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yl]carbonylaminopropionic acid;
2-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenoxy]-ethanol;
3-[2-dimethylamino-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-propan-1-ol;
3-{6-[4-(1-methyl)ethoxyphenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}propanol;
2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
3-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-propane-1,2-diol;
3-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-propan-1-ol;
3-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-propan-2-ol;
2-[1-methyl-5-(2H-tetrazol-5-yl)-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
2-[1-methyl-5-(2-methyl-2H-tetrazol-5-yl)-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
2-[1-methyl-5-(1-methyl-1H-tetrazol-5-yl)-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-ethanone;
2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
2-[5-(2-methoxy-1-methyl-ethoxy)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
2-[1-methyl-5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
3-[6-methoxy-1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-propane-1,2-diol;
6-methoxy-1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-ol;
2-(5-methoxy-1-methyl-1H-indol-3-yl)-4-phenyl-1H-pyrrolo[2,3-b]pyridine;
2-[5-(pyridin-4-yl)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile;
4-chloro-2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-ylamine;
N-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-methanesulfonamide;
N-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yl]-acetamide;
{1-[5-(1-hydroxymethyl-cyclobutoxy)-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-cyclobutyl}-methanol;
{1-[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yloxy]-cyclobutyl}-methanol;
2-[6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]ethyl-2H-tetrazole;
3-[6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2H-propionitrile;
3-[6-(4-tert-butylphenyl-5-pyrrolo[2,3-b]pyrazin-7-yl]-propionamide;
3-[6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propionic acid;
3-{6-[4-(1-methyl)ethoxyphenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionic acid;
3-[6-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]propionic acid;
3-[6-(4-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]propionic acid;
3-[6-(4-tert-butyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-ol;
[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenoxy]acetic acid ethyl ester;
2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)phenol;
3-fluoro-2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
3-{6-(4-hydroxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionic acid;
ethyl 3-{6-(4-hydroxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl}propionate;
2-(5-methoxy-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile;
6-(4-methylsulfinylphenyl)-5H-pyrrolo[2,3-b]pyrazine;
6-(4-methylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine;
3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}acetamide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}cyclopropylcarboxylic acid amide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}butyramide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}methoxyacetamide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}thien-2ylcarboxylic acid amide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}-Nxe2x80x2-propyl urea;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}-Nxe2x80x2-carboethoxymethyl urea;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}-Nxe2x80x2,Nxe2x80x2-diethyl urea;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}methanesulfonamide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}thien-2-ylsulfonamide
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}dimethylisoxazol-4-ylsulfonamide;
N-{3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl}1-methylimidazol-4-ylsulfonamide;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Preferred compounds of the invention are:
6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (compound denoted as A1-B1-C1);
1-[1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-yloxy]-cyclobutanecarboxylic acid amide(compound denoted as A2-B1-C31);
2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile(compound denoted as A3-B1-C28);
{1-[1-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-1H-indol-5-yloxy]-cyclobutyl}-methanol(compound denoted as A1-B1-C28);
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention block kinase catalytic activity according to tests described in the literature and described in vitro procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of protein kinase inhibitors (e.g. Syk, FAK, KDR or Aurora2). For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example asthma: inflammatory dermatoses (e.g. psoriasis, dematitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease); allergic rhinitis and allergic conjunctivitis; joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. The compounds are also useful in the treatment of Chronic Obstructive Pulmonary Disease (COPD), acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus, graft v host disease and other transplant associated rejection events, cancers and tumours (such as colorectal, prostate, breast, thyroid, colon and lung cancers) and inflammatory bowel disease. Additionally, the compounds are useful as tumor anti-angiogenic agents.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of psoriasis
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
A special embodiment of the therapeutic methods of the present invention is the treating of cancers and tumours.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of a protein kinase inhibitor (e.g. Syk, FAK, KDR or Aurora2) for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting the catalytic activity a protein kinase, such as Syk, FAK, KDR or Aurora2, and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed in pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of formula (I) wherein R1, R2 and R3 are as hereinbefore defined, and X1 is N or CH may be prepared by application or adaptation of the procedures described by Davis et al Tetrahedron, 1992, 48, page 939-952, for example:
(i) reaction of compounds of formula (III): 
xe2x80x83wherein R2 and R3 are as hereinbefore defined and X1 is N or CH, with a suitable base, such as lithium diisopropylamide (or butyllithium), in an inert solvent, such as tetrahydrofuran, and at a temperature from about xe2x88x9226xc2x0 C.;
(ii) treatment of the resulting anion with nitrites of formula (IV):
R1xe2x80x94CNxe2x80x83xe2x80x83(IV) 
xe2x80x83wherein R1 is as defined hereinbefore at a temperature at about xe2x88x9215xc2x0 C. to about room temperature.
This procedure is particularly suitable for the preparation of compounds of formula (I) where R1 is optionally substituted N-methylindol-3-yl, R2 and R3 are hydrogen and X1 is N or CH.
Compounds of formula (I) wherein R1, R2, R3 and X1 are as hereinbefore defined may also be prepared by application or adaptation of the procedure described by Chang and Bag, J.Org.Chem., 1995, 21, pages 7030-7032, for example reaction of compounds of formula (V): 
wherein R1, R2, R3 and X1 are as hereinbefore defined, and X2 is a halogen, preferably iodine, atom or a triflate group, with a boronic acid of formula (VI):
R1xe2x80x94B(OH)2xe2x80x83xe2x80x83(VI) 
wherein R1 is as defined hereinbefore. The coupling reaction may conveniently be carried out for example in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and sodium bicarbonate, in aqueous dimethylformamide at a temperature up to reflux temperature.
Compounds of the invention may also be prepared by interconversion of other compounds of the invention.
Thus, for example, compounds of formula (I) containing a carboxy group may be prepared by hydrolysis of the corresponding esters. The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example compounds of formula (I) containing a carboxy group may be prepared by acid catalysed removal of the tert-butyl group of the corresponding tert-butyl esters using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
As another example compounds of formula (I) containing a carboxy group may be prepared by hydrogenation of the corresponding benzyl esters. The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
As another example of the interconversion process, compounds of formula (I) containing a xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2 group may be prepared by coupling compounds of formula (I) containing a carboxy group with an amine of formula HNY1Y2 to give an amide bond using standard peptide coupling procedures, for example coupling in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature. The coupling may also be brought about by reaction of compounds of formula (I) containing a carboxy group with N-{(dimethylamino)(1H-1,2,3-triazaolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide in the presence of a suitable base, such as diisopropylethylamine, in an inert solvent, such as dimethylformamide, and at a temperature at about room temperature, followed by reaction with an amine of formula HNY1Y2 (ammonium chloride can be used for the preparation of compounds of formula (I) containing a xe2x80x94C(xe2x95x90O)xe2x80x94NH2 group).
As another example of the interconversion process, compounds of formula (I) containing a xe2x80x94CH2OH group may be prepared by the reduction of corresponding compounds of formula (I) containing a xe2x80x94CHO or xe2x80x94CO2R7 (in which R7 is lower alkyl) group. For example, the reduction may conveniently be carried out by means of reaction with lithium aluminium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature from about room temperature to about reflux temperature.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94CO2Me may be prepared by:
(i) treating compounds of formula (I) in which R1 is aryl or heteroaryl substituted by hydroxy, with N-phenyltrifluoromethanesulfonimide in the presence of a suitable base, such as triethylamine, in an inert solvent, such as dichloromethane, and at a temperature at about xe2x88x9278xc2x0 C.;
(ii) reaction of the resulting triflate with carbon monoxide in the presence of a suitable catalyst (e.g. palladium acetate), 1,3-bis(diphenylphosphino)propane, triethylamine and methanol, in an inert solvent, such as dimethylformamide at a pressure of about 1 atmosphere, and at a temperature at about room temperature.
This procedure is particularly suitable for the preparation of compounds of formula (I) in which R1 is 5-carboxymethyl-N-methylindol-3-yl.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94SO2NY1Y2 may be prepared by:
(i) treating compounds of formula (I) in which R1 is aryl or heteroaryl substituted by hydroxy, with N-phenyltrifluoromethanesulfonimide as described hereinabove;
(ii) treating the resulting triflate with tertiary-butylmercaptan in the presence of sodium tertiary-butoxide, palladium acetate, lithium chloride and R(+)-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl in an inert solvent, such as toluene, and at a temperature at about 110-120xc2x0 C.;
(iii) reaction of the resulting compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94StBu, with trifluoroacetic acid and mercuric acetate, in an inert solvent, such as toluene, and at a temperature at about room temperature, followed by treatment with hydrogen sulfide;
(iv) reaction of the resulting compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94SH, with chlorine in aqueous acetic acid at a temperature at about room temperature;
(v) reaction of the resulting compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94SO2Cl, with an amine of formula HNY1Y2.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by aryl (or heteroaryl) may be prepared by treating compounds of formula (I) in which R1 is aryl or heteroaryl substituted by hydroxy with N-phenyltrifluoromethanesulfonimide as described hereinabove followed by reaction of the resulting triflate with an aryl (or heteroaryl) boronic acid ester in the presence of a suitable catalyst (e.g. palladium tetrakis(triphenylphosphine) and aqueous sodium bicarbonate, in an inert solvent, such as dimethylformamide, and at a temperature at about 120-150xc2x0 C.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by hydroxy may be prepared by reaction of the corresponding compounds of formula (I) in which R1 is aryl or heteroaryl substituted by methoxy with a Lewis acid, such as boron tribromide, in an inert solvent, such as dichloromethane and at a temperature from about 0xc2x0 C. to about room temperature.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94OR4 may be prepared by alkylation the corresponding compounds of formula (I) in which R1 is aryl or heteroaryl substituted by hydroxy, with compounds of formula (VII):
R4xe2x80x94X3xe2x80x83xe2x80x83(VII) 
wherein R4 is as hereinbefore defined and X3 is a halogen, preferably bromo, atom, or a tosyl group, using standard alkylation conditions. The alkylation may for example be carried out in the presence of a base, such as an alkali metal carbonate (e.g. potassium carbonate or cesium carbonate), an alkali metal alkoxide (e.g. potassium tertiary butoxide) or alkali metal hydride (e.g. sodium hydride), in dimethylformamide, or dimethyl sulfoxide, at a temperature from about 0xc2x0 C. to about 100xc2x0 C.
Alternatively compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94OR4 may be prepared by reaction of the corresponding compounds of formula (I) in which R1 is aryl or heteroaryl substituted by hydroxy with the appropriate alcohol of formula (VIII):
R4xe2x80x94OHxe2x80x83xe2x80x83(VIII) 
wherein R4 is as hereinbefore defined in the presence of a triarylphosphine, such a triphenylphosphine, and a dialkyl acetylenedicarboxylate, such as diisopropylacetylenedicarboxylate or dimethylacetylenedicarboxylate, in an inert solvent, such as toluene, and at a temperature at about room temperature. This procedure is particularly suitable for the preparation of compounds of formula (I) in which R1 is heteroaryl substituted by xe2x80x94OR4.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94OR4, where R4 is propyl substituted by hydroxy, may be prepared by reaction of the corresponding compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94OR4, where R4 is propenyl, with borane followed by reaction with hydrogen peroxide in the presence of sodium hydroxide. This procedure is particularly suitable for the preparation of compounds of formula (I) in which R1 is indolyl substituted by xe2x80x94OCH2CH(CH3)OH and xe2x80x94OCH2CH2CH2OH.
As another example of the interconversion process, compounds of formula (I) in which R1 is aryl or heteroaryl substituted by xe2x80x94OR4, where R4 is a 1,3-dihydroxyalkylene group, may be prepared by reaction of the corresponding compounds where R4 is alkenyl with osmium tetroxide in the presence of 4-methyl-morpholine N-oxide. The reaction may conveniently be carried out in an inert solvent, such as acetone, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (Ia) in which R9 is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted by xe2x80x94C(xe2x95x90O)NY1Y2, xe2x80x94OR6, xe2x80x94C(xe2x95x90O)xe2x80x94OR7, xe2x80x94NY1Y2 may be prepared by alkylation of the corresponding compounds of formula (Ia) in which R9 is hydrogen, with the appropriate halide of formula (IX):
R9xe2x80x94X4 xe2x80x83xe2x80x83(IX) 
wherein R9 is alkyl, alkenyl, cycloalkyl, heterocycloalkyl, or alkyl substituted by xe2x80x94C(xe2x95x90O)NY1Y2, xe2x80x94OR7, xe2x80x94C(xe2x95x90O)xe2x80x94OR5, xe2x80x94NY1Y2 and X4 is a halogen, preferably bromine, atom, using standard alkylation conditions for example those described hereinbefore.
As another example of the interconversion process, compounds of formula (I) containing a xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94NY3Y4 group in which R6 and Y3 are both hydrogen and Y4 is as hereinbefore defined may be prepared by reaction of the corresponding compounds of formula (I) containing an amino group with an isocyanate of formula Oxe2x95x90Cxe2x95x90NY4 in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (I) containing sulfoxide linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulfate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0xc2x0 C. and room temperature. This latter method is preferred for compounds containing an acid-labile group.
As another example of the interconversion process, compounds of formula (I) containing sulfone linkages may be prepared by the oxidation of corresponding compounds containing xe2x80x94Sxe2x80x94 or sulfoxide linkages. For example, the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
As another example of the interconversion process, compounds of formula (I) containing a cyano group may be prepared by reaction of the corresponding compounds of formula (I) containing a xe2x80x94C(xe2x95x90O)xe2x80x94NH2 group with phosphorus pentachloride in the presence of triethylamine. The reaction may conveniently be carried out in an inert solvent, such as tetrahydrofuran, and at a temperature at about reflux temperature.
As another example of the interconversion process, compounds of formula (I) containing a tetrazolyl group may be prepared by reaction of the corresponding compounds of formula (I) containing a cyano group with azidotributyltin. The reaction may conveniently be carried out in an inert solvent, such as toluene, and at a temperature at about reflux temperature.
As another example of the interconversion process, compounds of formula (I) in which R2 is a fluoro may be prepared by reaction of the corresponding compounds of formula (I) in which R2 is hydrogen with methyl magnesium bromide (in an inert solvent, such as tetrahydrofuran, and at a temperature at about 0xc2x0 C.) followed by reaction with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) at a temperature from about 0xc2x0 C. to about reflux temperature.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Compounds of formula (IV) wherein R1 is as defined hereinbefore may be prepared by reaction of the corresponding compounds of formula (1):
R1xe2x80x94CHOxe2x80x83xe2x80x83(1) 
wherein R1 is as hereinbefore defined, with hydroxylamine hydrochloride in an inert solvent, such as dimethylformamide, and at a temperature at about 150xc2x0 C.
Compounds of formula (IV) wherein R1 is represented by the formula (IIa), in which R10 and p are as hereinbefore defined and R9 is alkyl, alkenyl, cycloalkyl or alkyl substituted by xe2x80x94C(xe2x95x90O)NY1Y2, xe2x80x94OR4, xe2x80x94C(xe2x95x90O)xe2x80x94OR7, xe2x80x94NY1Y2, may be prepared by alkylation of the corresponding 1H-indoles of formula (IV) wherein R1 is represented by the formula (IIa), in which R10 and p are as hereinbefore defined and R9 is hydrogen, with the appropriate (optionally substituted)alkyl-, alkenyl- or cycloalkyl-halide using standard alkylation conditions. The alkylation may for example be carried out in the presence of a base, such as an alkali metal carbonate, e.g. potassium carbonate, or alkali metal hydride, e.g. sodium hydride, in an inert solvent, such as dimethylformamide or dimethyl sulfoxide, at a temperature from about room temperature to about 100xc2x0 C.
Compounds of formula (IV) wherein R1 is 5,6,7,8-tetrahydroindolizin-1-yl may be prepared by:
(i) reaction of piperidine-2-carboxylic acid with formic acid and acetic anhydride at a temperature at about room temperature;
(ii) treatment of the resulting sodium-1-formyl-piperidine-2-carboxylate with 4-toluenesulfonyl chloride in an inert solvent, such as dichloromethane, and at a temperature at about room temperature;
(iii) reaction with acrylonitrile in the presence of triethylamine at a temperature at about room temperature.
Compounds of formula (1) wherein R1 is as defined hereinbefore may be prepared by formylation of compounds of formula (2):
R1xe2x80x94Hxe2x80x83xe2x80x83(2) 
wherein R is as defined hereinbefore using standard reaction conditions, for example using a Vilsmeier-Haack formylation reaction with phosphorus oxychloride in dimethylformamide. This procedure is particularly suitable for the preparation of compounds of formula (1) where R1 is optionally substituted N-methylindol-3-yl.
Compounds of formula (V) wherein R2, R3 and X1 are as hereinbefore defined and X2 is an iodine atom, may be prepared by iodination of compounds of formula (3): 
wherein R2, R3 and X1 are as hereinbefore defined. The iodination reaction may conveniently be carried out by the application or adaptation of the procedure described by Saulnier and Gribble, J.Org.Chem., 1982, 47, 1982, for example by treatment of compounds of formula (3) with lithium diisopropylamide in an inert solvent, such as tetrahydrofuran, and at a temperature at about xe2x88x9278xc2x0 C., followed by reaction of the resulting anion with iodine. This reaction is conveniently carried out with the indole NH protected with for example a tosyl group.
Compounds of formula (3) wherein R2, R3 and X1 are as hereinbefore defined may be prepared by cyclisation of compounds of formula (4): 
wherein R2, R3 and X1 are as hereinbefore defined. The cyclisation reaction may conveniently be carried out in the presence of an alkali metal alkoxide, such as sodium ethoxide, in an inert solvent, such as ethanol, and at a temperature from about room temperature to about reflux temperature.
Compounds of formula (3) wherein R3 and X1 are as hereinbefore defined and R2 is hydrogen may be prepared by cyclisation of compounds of formula (5): 
wherein R3 and X1 are as hereinbefore defined. The cyclisation reaction may conveniently be carried out in the presence of sodamide, in N-methylaniline and at a temperature from about 120xc2x0 C. to about 200xc2x0 C.
Compounds of formula (3) wherein R3 and X1 are as hereinbefore defined and R2 is methyl (or C1-4alkyl optionally substituted by xe2x80x94Z1R8, in which Z1 and R8 as hereinbefore defined) may be prepared by cyclisation of compounds of formula (6): 
wherein R3 and X1 are as hereinbefore defined, R11 is hydrogen (or C1-3alkyl optionally substituted by xe2x80x94Z1R8, in which Z1 and R8 as hereinbefore defined) and X5 represents a halogen, preferably a bromine, atom, or a triflate group. The cyclisation may conveniently be carried out in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0), a tertiary amine, such as triethylamine, and a triarylphosphine, such as triphenylphosphine, in an inert solvent, such as dimethylformamide and at a temperature at about 60xc2x0 C. to about 120xc2x0 C. This procedure is particularly suitable for the preparation of compounds of formula (3) wherein R3 and X1 are as hereinbefore defined, X1 is N and R2 is Cxe2x80x94CH3.
Compounds of formula (3) wherein R3, R2 and X1 are as hereinbefore defined may be prepared by:
(i) reaction of compounds of formula (7): 
xe2x80x83wherein R3 and X1 are as hereinbefore defined and X6 is a halogen, preferably iodine, atom with acetylenes of formula (8):
R2xe2x80x94Cxe2x89xa1Cxe2x80x94SiMe3xe2x80x83xe2x80x83(8) 
xe2x80x83wherein R2 is as hereinbefore defined, in the presence of a complex metal catalyst such as [1,1xe2x80x2-bis(diphenylphosphino)-ferrocene]palladium (II) chloride, lithium chloride and sodium carbonate, in an inert solvent, such as dimethylformamide, and at a temperature up to about 100xc2x0 C.
(ii) desilylation.
Compounds of formula (4) wherein R2, R3 and X1 are as hereinbefore defined may be prepared by reaction of compounds of formula (9): 
wherein R2, R3 and X1 are as hereinbefore defined with a mixture of formic acid and acetic anhydride.
Compounds of formula (5) wherein R3 and X1 are as hereinbefore defined may be prepared by reaction of the corresponding compounds of formula (9) wherein R3 and X1 are as hereinbefore defined and R2 is hydrogen with triethylorthoformate, in the presence of an acid catalyst, such as hydrogen chloride, in ethanol and at a temperature from about room temperature to about reflux temperature.
Compounds of formula (6) wherein R3, R11 and X1 are as hereinbefore defined and X5 is a halogen atom may be prepared by alkylation of compounds of formula (7) wherein R3, X1 and X6 are as hereinbefore defined with the appropriate alkenyl halide of formula (10):
R11CHxe2x95x90CHxe2x80x94CH2xe2x80x94X7xe2x80x83xe2x80x83(10) 
wherein R11 is as hereinbefore defined and X7 is a halogen, preferably bromine, atom. The alkylation may conveniently be carried out in the presence of an alkali metal hydride, such as sodium hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
Compounds of formula (7) wherein R3 and X1 are as hereinbefore defined and X6 is a bromine atom, may be prepared by bromination of compounds of formula (11): 
wherein R3 and X1 are as hereinbefore defined, in dimethylsulfoxide.
Compounds of formula (7) wherein R3 and X1 are as hereinbefore defined and X5 is an iodine atom, may be prepared by iodination of compounds of formula (11) wherein R3 and X1 are as hereinbefore defined. The iodination may be carried out by the application or adaptation of the method of W-W. Sy, Synth.Comm., 1992, 22, pages 3215-3219.
Compounds of formula (V) wherein R1, R2, R3 and X1 are as hereinbefore defined and X5 is a triflate group may be prepared by reaction of compounds of formula (12): 
wherein R2, R3 and X1 are as hereinbefore defined, with triflic anhydride in the presence of Hunigs base, in an inert solvent, such as dichloromethane, and at a temperature at about 0xc2x0 C. This reaction is conveniently carried out with the indole NH protected with for example a tosyl group.
Compounds of formula (12) wherein R2, R3 and X1 are as hereinbefore defined may be prepared by reaction of compounds of formula (13): 
wherein R3 and X1 are as hereinbefore defined with meta-chloroperbenzoic acid, in an inert solvent, such as dichloromethane, and at a temperature at about 5xc2x0 C. This reaction is conveniently carried out with the indole NH protected with for example a tosyl group.
Compounds of formula (13) wherein R3 and X1 are as hereinbefore defined may be prepared by reaction of compounds of formula (14): 
wherein R3 and X1 are as hereinbefore defined with lithium diisopropylamide, in an inert solvent, such as tetrahydrofuran, followed by reaction with dimethylformamide and at a temperature at about xe2x88x9278xc2x0 C. This reaction is conveniently carried out with the indole NH protected with for example a tosyl group.
Compounds of formula (14) wherein R3 and X1 are as hereinbefore defined may be prepared by reaction of compounds of formula (7) wherein R3 and X1 are as hereinbefore defined and X6 is iodo, with trimethylsilylacetylene in the presence of a complex metal catalyst such as [1,1xe2x80x2-bis(diphenylphosphino)-ferrocene]palladium (11) chloride, followed by desilylation.
Compounds of formula (VI) wherein R1 is as defined hereinbefore may be prepared by: reaction of compounds of formula (15):
R1xe2x80x94X8xe2x80x83xe2x80x83(15) 
wherein R is as defined hereinbefore and X8 is a halogen, preferably bromine, atom, in the presence of tributylborate, with a suitable base, such as butyllithium, in an inert solvent, such as tetrahydrofuran, and at a temperature at about xe2x88x92100xc2x0 C.
Compounds of formula (VI) wherein R1 is as defined hereinbefore may also be prepared by treatment of compounds of formula (15), wherein R1 is as defined hereinbefore and X8 is a xe2x80x94HgOAc group, with borane, in an inert solvent, such as tetrahydrofuran, and at a temperature at about room temperature.
Compounds of formula (15) wherein R1 is optionally substituted indol-3-yl and X8 is a bromine atom may be prepared by reaction of optionally substituted indoles with bromine in an inert solvent, such as dimethylformamide, and at a temperature at about room temperature.
Compounds of formula (13) wherein R1 is optionally substituted indol-3-yl and X8 is a xe2x80x94HgOAc group may be prepared by reaction of optionally substituted indolines with mercuric acetate in glacial acetic acid at a temperature at about room temperature.
The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
400M Hz 1H nuclear magnetic resonance spectra (NMR) were recorded on a Varian Unity INOVA machine. In the nuclear magnetic resonance spectra (NMR) the chemical shifts (xcex4) are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances: s=singlet; d=doublet; t=triplet; m=multiplet; q=quartet; dd=doublet of doublets; ddd=doublet of double doublets.
The high pressure liquid chromatography retention times (HPLC: RT values) were determined by: (i) Method A, C18 Phenomenex (150xc3x974.6 mm) column using gradient elution with a mixture of acetonitrile and water with 0.1% trifluoroacetic acid as the mobile phase (0-1 minute 5% acetonitrile; 1-12 minutes ramp up to 95% acetonitrile; 12-14.95 minutes 95% acetonitrile; 14.95-15 minutes 0% acetonitrile); or Method B, YMC ODS-AQ (2xc3x9750 mm) column using gradient elution with a mixtures of acetonitrile and water with 0.1% formic acid as the mobile phase [95/5/0.1% (A) to 5/95/0.1% (B)] and a flow rate of 0.4 mL/minute); or Method C, what column ?? column using gradient elution with a mixture of acetonitrile and water with 0.1% formic acid as the mobile phase (95/5/0.1%, water/acetonitrile/formic acid for 0.1 minute linear gradient to 5/95/0.1%, water/acetonitrile/formic acid at 2 minutes and hold until 3.5 minutes).
The thin layer chromatography (TLC) RF values were determined using Merck silica plates.